PROJECT SUMMARY Cardiovascular disease is responsible for 1 in 4 deaths, or 650,000 Americans, every year. It is the leading cause of death in the United States. Ruptured atherosclerotic plaques are the main cause of acute coronary events, and it is of lethal consequence. Clinically, early detection of the latent vulnerability of plaques is the first line of defense against such deadly circumstances, and it relies on visualizing both tissue structural and biomechanical properties. Accurate characterization of a plaque lesion can facilitate better treatment management by further our understanding in the disease progression. The long-term objective of this proposal is to develop a multimodal intravascular imaging system that combines optical coherence tomography (OCT), ultrasound imaging (US), and shear-wave-based optical coherence elastography (OCESW) for studying and characterizing plaque vulnerability. The proposed system, IVOCT-US-OCESW, is built upon the ARF-OCE technology developed in the preceding proposal, with several significant technical advancements that will further facilitate its clinical translation. The proposed IVOCT-US- OCESW system unifies the high spatial resolution and extended penetration depth of the 1.7-m OCT, the broad imaging depth of US, and the enhanced biomechanical contrast of OCESW. It will provide physicians a powerful clinical instrument for studying, diagnosing, and managing vulnerable plaques. The multimodal probe only requires a single disposable guide wire and catheter, thereby reducing the costs, procedure length, associated risks, and X-ray exposure. Our specific aims are to: 1) Design and construct a multimodal IVOCT-US-OCESW imaging probe; 2) Develop the IVOCT-US-OCESW system featuring a 4-MHz, 1.7-m laser; 3) Establish a scanning protocol and algorithms for biomechanical property quantification; 4) Demonstrate the efficacy of the proposed system in normal and diseased animal models. We expect the development of the proposed high-speed, high-penetration-depth, and high-sensitivity IVOCT-US-OCESW system and probe to have significant impact to both basic science and clinical understanding of plaque pathogenesis. This will enhance the clinicians? ability to identify vulnerable lesions, tailor interventional therapy, and monitor disease progression. More importantly, it will be a powerful tool that provides a quantitative means to benchmark and evaluate new medical devices and therapies.